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The underlying causes of functional impairment are poorly understood and, therefore, we sought to investigate the contribution of genetic factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a cross-sectional analysis of sociodemographic, clinical and genetic information of people with COPD. Hierarchical clustering based on functional capacity (6-minute walk test and 1-minute sit-to-stand test) and muscle strength (quadriceps isometric muscle strength and handgrip muscle strength) was performed. A genome-wide association study (GWAS) was performed using cluster assignment as phenotype. Polygenic risk scores (PRSs) were calculated for each variable. Genomic-derived data was used to construct a model to predict functional impairment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two clusters were identified among 245 individuals. Cluster 1 (n=104) was composed of younger, less symptomatic patients, with preserved functional capacity and muscle strength, whereas cluster 2 (n=141) included those older, more symptomatic, with reduced functional capacity and muscle weakness. GWAS identified two polymorphisms suggestively associated with functional impairment, mapped to<jats:italic>xanthine dehydrogenase<\/jats:italic>. Cluster 2 was enriched in individuals with risk alleles for rs1991541 and rs10524730, and lower PRSs for functional capacity and muscle strength. A prediction model using genomic-derived data was constructed (n=159) and tested (n=37), yielding an area under the curve of 0.87 (0.76\u20130.99).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Genetic factors are significantly associated with functional impairment in COPD. The incorporation of genetic information, particularly PRSs, into a predictive model offers a promising avenue for timely identifying individuals at greater risk of functional decline, potentially facilitating personalised and preventive interventions. Further studies on independent external cohorts are needed to validate our model.<\/jats:p><\/jats:sec>","DOI":"10.1136\/thorax-2024-222142","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T18:23:25Z","timestamp":1738175005000},"page":"283-290","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Functional impairment in COPD can be predicted using genomic-derived data"],"prefix":"10.1136","volume":"80","clinical-trial-number":[{"clinical-trial-number":"nct03701945","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03799666","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02053870","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0699-335X","authenticated-orcid":false,"given":"Rui","family":"Mar\u00e7alo","sequence":"first","affiliation":[]},{"given":"Guilherme","family":"Rodrigues","sequence":"additional","affiliation":[]},{"given":"Miguel","family":"Pinheiro","sequence":"additional","affiliation":[]},{"given":"Sonya","family":"Neto","sequence":"additional","affiliation":[]},{"given":"Sofia L","family":"Marques","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Sim\u00e3o","sequence":"additional","affiliation":[]},{"given":"Vit\u00f3ria","family":"Martins","sequence":"additional","affiliation":[]},{"given":"L\u00edlia","family":"Andrade","sequence":"additional","affiliation":[]},{"given":"Maria Aurora","family":"Mendes","sequence":"additional","affiliation":[]},{"given":"Manuel","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Vera","family":"Afreixo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4980-6200","authenticated-orcid":false,"given":"Alda","family":"Marques","sequence":"additional","affiliation":[]},{"given":"Gabriela","family":"Moura","sequence":"additional","affiliation":[]}],"member":"239","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"2025041509351456000_80.5.283.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00511-7"},{"key":"2025041509351456000_80.5.283.2","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2010.137661"},{"key":"2025041509351456000_80.5.283.3","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201609-733AS"},{"key":"2025041509351456000_80.5.283.4","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.00010114"},{"key":"2025041509351456000_80.5.283.5","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00131612"},{"key":"2025041509351456000_80.5.283.6","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2006.062026"},{"key":"2025041509351456000_80.5.283.7","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201309-1634ST"},{"key":"2025041509351456000_80.5.283.8","doi-asserted-by":"crossref","DOI":"10.3390\/ijms24076454","article-title":"Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting","volume":"24","author":"Henrot","year":"2023","journal-title":"Int J Mol Sci"},{"key":"2025041509351456000_80.5.283.9","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S134161"},{"key":"2025041509351456000_80.5.283.10","doi-asserted-by":"crossref","DOI":"10.1186\/s12931-022-01954-6","article-title":"COPD profiles and treatable traits using minimal resources: identification, decision tree and stability over time","volume":"23","author":"Marques","year":"2022","journal-title":"Respir Res"},{"key":"2025041509351456000_80.5.283.11","doi-asserted-by":"crossref","DOI":"10.1186\/s12931-023-02339-z","article-title":"Responsiveness to pulmonary rehabilitation in COPD is associated with changes in microbiota","volume":"24","author":"Melo-Dias","year":"2023","journal-title":"Respir Res"},{"key":"2025041509351456000_80.5.283.12","doi-asserted-by":"crossref","DOI":"10.1186\/s12889-019-7045-1","article-title":"Improving access to community-based pulmonary rehabilitation: 3R protocol for real-world settings with cost-benefit analysis","volume":"19","author":"Marques","year":"2019","journal-title":"BMC Public Health"},{"key":"2025041509351456000_80.5.283.13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3390\/healthcare10010119","article-title":"Long-Term Maintenance Strategies after Pulmonary Rehabilitation: Perspectives of People with Chronic Respiratory Diseases, Informal Carers, and Healthcare Professionals","volume":"10","author":"Souto-Miranda","year":"2022","journal-title":"Healthcare (Basel)"},{"key":"2025041509351456000_80.5.283.14","unstructured":"Global initiative for chronic obstructive lung disease . 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